Risk of all-cause mortality or hospitalization for pneumonia associated with inhaled β2-agonists in patients with asthma, COPD or asthma-COPD overlap

β2-agonists provide necessary bronchodilatory action, are recommended by existing clinical practice guidelines and are widely prescribed for patients with these conditions. We examined the risk of all-cause mortality and hospitalization for pneumonia associated with long-or short-acting β2-agonists (LABA or SABA) or ICS (inhaled corticosteroids)/LABA use. In a nested case–control of 185,407 patients, we found no association between β2-agonist use and the risk of pneumonia in patients with asthma, COPD, or asthma-COPD overlap. In contrast, new SABA [HR 1.82 (95% CI 1.04–3.20)] or LABA [HR 2.77 (95% CI 1.22–6.31)] use was associated with an increased risk of all-cause mortality compared to ICS use in COPD patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-022-02295-0.


Introduction
Asthma is a significant public health problem worldwide, causing excess morbidity, mortality, and economic costs [1]. Likewise, chronic obstructive pulmonary disease (COPD) was ranked as the 4th leading cause of death in 2019 and caused considerable morbidity and substantial health care costs [2]. Furthermore, an increasing number of people are affected by asthma-COPD overlap, with 15 to 45% of older adults initially diagnosed with COPD or asthma [3].
β2-agonists provide necessary bronchodilatory action and are recommended by existing clinical practice guidelines, and are widely prescribed for patients with these conditions [4,5]. Nevertheless, information on the risk of all-cause mortality and pneumonia is limited, and the results are inconsistent [6,7]. Given the steadily growing trend of β2-agonists-based drug prescriptions (58-185%) in patients with asthma and, more specifically, COPD [8,9], there is a need to investigate whether these widely prescribed drugs are associated with an increased risk of all-cause mortality and hospitalization for pneumonia.

Methods
This study was conducted using the United Kingdom Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics (HES) and Office of National Statistics (ONS) databases, representing the UK's geographical distribution [10,11]. The study protocol was approved by the Independent Scientific Advisory Committee of the CPRD (ISAC 18_005RA) and ethical approval was obtained from Health Research Ethics Board at Memorial University, St. John's, Canada. The study cohort included all males and females diagnosed with asthma, COPD, or asthma-COPD overlap in the CPRD aged 18 or over with a first-ever prescription for a LABA, SABA, combination therapy of ICS/LABA, ICS, LAMA or SAMA.
A risk-set sampling method was used to match the case with a random sample from the risk set for each case occurring during the study follow-up. For each case, we randomly selected up to 10 controls within the cohort on the basis of sex, age (± 1 year), date of cohort entry (± 180 days), and duration of follow-up. The case's index date became the index date for those matched controls selected randomly at the risk-set. The schematic design of the nested case-control analysis employed is shown in Fig. 1.
Details on the study cohort, case-control selection, exposure assessment, covariates, statistical and sensitivity analyses can be found in the Additional file 1.
As per Tables 1 and 2, there were 334 all-cause mortality cases, including 139, 153, and 42 deaths among patients with asthma, COPD, and asthma-COPD overlap, respectively, and 505 new hospitalizations for pneumonia, representing 332, 133, and 40 events among patients with asthma, COPD, and asthma-COPD overlap, respectively. The mean ± SD age at cohort entry with all-cause mortality casepatients was 69.6 ± 14.8, 75.9 ± 9.7 and 75.9 ± 8.0 years for asthma, COPD and asthma-COPD overlap, respectively, and 53.1 ± 19.9, 72.7 ± 9.3 and 72.4 ± 14.3 years for pneumonia case-patients. The baseline characteristics of cases and controls for all-cause mortality ( Table 1) and pneumonia (Table 2) are presented.
Among cases with all-cause mortality, controls were less likely to be females than males. On the other hand, Pneumonia patients were more likely to be females with asthma, whereas COPD and asthma-COPD overlap patients were more likely to be males. Except for patients with COPD, case patients were more likely to be obese regarding all-cause mortality. Cases were also more likely to be current smokers, the most deprived, have at least two or more comorbidities (Charlson Index), and prescribed more loop diuretics, aspirin, opioids, and insulin. However, the baseline characteristics of case patients with systolic blood pressure, deprivation (material deprivation), and NSAID prescription were fairly balanced across OADs. Table 3 shows the multivariate analyses of all-cause mortality and pneumonia after accounting for all baseline variables listed in Tables 1 and 2. Cells with fewer than five events are not permitted to be displayed in the table due to CPRD confidentiality policies.    Table 3, there were no statistically significant associations between the risk of pneumonia and   β 2 -agonist-based drugs among patients with asthma, COPD, and asthma-COPD overlap, respectively, after adjusting for potential confounders.

Sensitivity analyses
Additional file 1: Fig. S2 depicts the results of our sensitivity analyses by using different grace periods for the sub-cohorts of COPD and asthma for the exposure contrast of SABA versus SAMA and the risk of all-cause mortality. The overall results of our sensitivity analyses for all-cause mortality for COPD (top panel) were consistent with those of our primary analyses. Pertaining to asthma patients (bottom panel), the adjusted HR generated in our primary analyses was similar to the one generated in our fixed-effect analysis.

Discussion
This real-world population-based nested case-control study suggests that among patients with COPD who newly started inhaled β 2 -agonists-based drugs, SABA or LABA monotherapy was associated with a 1.8-fold and 2.8-fold increase in all-cause mortality, respectively, compared with ICS monotherapy. Regarding the risk of pneumonia, our findings indicate that the use of β 2agonists-based drugs (SABA) was not associated with an increased risk of pneumonia compared to ICS or SAMA use in patients with asthma, COPD or asthma-COPD overlap. Finally, our findings remained consistent in several sensitivity analyses that explored the overall robustness of our study design and results. Short-acting β 2 -agonist bronchodilators help relieve COPD symptoms and may be a valuable marker of symptom severity [12]. Using data from 56 primary care and specialty centers in the United States, Dransfield et al. found that a mean SABA use of 3.3 puffs/day was associated with less severe airflow limitation (≥ 50% predicted forced expiratory volume in 1 s [FEV 1 ]), compared with 5.2 puffs/day in patients with more severe airflow limitation (< 50% predicted FEV 1 ) [13]. It is widely believed that high supplementary SABA use indicates a significant   modest risk of exacerbation and hospitalization [14][15][16].
Our study being novel, is one of the most recent studies to quantify the risk of SABA among COPD patients; we observed that those who started SABA alone are 1.8 times more likely to be associated with all-cause mortality. Thus, the increased use of SABA monotherapy in COPD indicates its ineffectiveness rather than its association with disease severity. Notably, clinical guidelines recommend LAMA or LABA/ICS treatments over regular short-acting β 2 -agonist therapies for patients with exacerbations or persistent breathlessness, also known as patients with moderate or severe COPD [17]. Our observation of a 2.8-fold increased risk of all-cause mortality in COPD patients using LABA monotherapy is consistent with a meta-analysis of RCTs that observed a 2.5-fold increased risk of death in COPD patients using LABA monotherapy compared with placebo [18]. Although this meta-analysis was critiqued for not including the large dataset provided by the 3-year TORCH study, the most significant reductions in death were seen in the combination salmeterol/fluticasone propionate arm rather than the salmeterol monotherapy arm when compared to the placebo. Surprisingly, the sample size obtained after the TORCH study, following a safety call from a 'follow-up assessment, ' was entirely inadequate for generating a statistically significant result. The rate of all-cause mortality is regarded as a comprehensive prognostic indicator for any disease; it is dependable and widely regarded as the gold standard in determining the safety of a given therapy [19]. Although it is accepted that there is no cure for COPD, we believe it is time to shift the treatment paradigm for patients with COPD at risk of death from symptomatic relief to long-term treatment improvement. That being so, bronchodilators that alter airway smooth muscle tone are paramount to managing COPD symptoms and exacerbations [20].
Our findings indicate that the use of β 2 -agonist-based drugs is not associated with an increased risk of pneumonia compared with ICS among obstructive airway disease patients with asthma, COPD or asthma-COPD  overlap. Even after adjusting for several significant disease severity indicators, including the use of oral corticosteroids, respiratory antibiotics, GP visits, comorbidities, and co-medications, our study still lacks data on lung function tests, such as the FEV 1 and FEV 1 / FVC ratio, due to significant missing values or its unavailability. Concerning the COPD findings, this must be interpreted with caution due to the low event rates observed in both cases and controls, and differences in clinical presentation and treatment of COPD from country to country. Our findings also provide new evidence on the concerns of potential risk of pneumonia associated with short-acting bronchodilators (SABA, SAMA) among patients with asthma-COPD overlap. This is of particular concern regarding patients with the overlap disease whereby studies of asthma medications have excluded patients with COPD and vice versa.
In conclusion, starting LABA monotherapy or SABA monotherapy treatment was associated with an increased risk of all-cause mortality in patients with COPD. On the other hand, we observed no association between β 2 -agonist-based use and the risk of pneumonia in patients with asthma, COPD or asthma-COPD overlap.